HIV This Week

Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection.

Planque S, Salas M, Mitsuda Y, Sienczyk M, Escobar MA, Mooney JP, Morris MK, Nishiyama Y, Ghosh D, Kumar A, Gao F, Hanson CV, Paul S. AIDS. 2010;24:875-84

The aim of the study was to identify an HIV epitope suitable for vaccine development.  Diverse HIV-1 strains express few structurally constant regions on their surface   vulnerable to neutralizing antibodies. The mostly conserved CD4-binding site of gp120 is essential for host cell binding and infection by the virus.  Antibodies that recognize the CD4-binding site are rare, and one component of the CD4-binding site, the 421-433 peptide region, expresses B-cell superantigenic character, a property predicted to impair the anti-CD4-binding site adaptive immune response. IgA samples purified from the plasma of patients with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416-433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA. IgA preparations from three patients with subtype B infection for 19-21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D, and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416-433 peptide mimetic dependent on recognition of the CD4-binding residues located in this region. Immunoadsorption, affinity chromatography, and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4-binding site.  These observations identify the 421-433 peptide region as a vulnerable HIV site to which survivors of infection can produce powerful neutralizing antibodies. This indicates that the human immune system can bypass restrictions on the adaptive B cell response to the CD4-binding site, opening the route to targeting the 421-433 region for attaining control of HIV infection. 

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Editors’ note: Studying the immune response of 3 long-term survivors, who had contracted HIV as children from contaminated blood products 19-21 years previously, revealed a region of HIV that is structurally conserved in genetically diverse HIV strains around the world and is immunogenic, meaning that it stimulates a robust immune response. Purified plasma IgA preparations from each of these 3 patients who were infected with sub-type B neutralized 18 genetically diverse clinical isolates from subtypes A, B, C, D, and AE. This is exciting news because the search for such a conserved epitope, i.e. the part of the virus that is recognized by the immune system and to which an antibody binds, is a holy grail. The site is the 421-433 region of the CD4 binding site of the virus. Interestingly, the autoimmune disease systemic lupus erythematosus produces antibodies to this epitope - and HIV and lupus rarely co-exist.